Many cigarette smokers report that smoking helps them stay alert and improves their concentration. But does tobacco use confer a general cognitive advantage to smokers or do smokers perceive a boost in performance because nicotine can reverse transient cognitive deficits due to brief (between cigarettes) or prolonged (overnight) periods of tobacco abstinence? Our research in this area has attempted to answer this fundamental question: how does smoking or nicotine affect human cognition? In several studies, we demonstrated that tobacco abstinence can impair cognitive functioning and that, in general, smoking or nicotine reverses such deficits to smoking baseline levels. These data strongly suggest that this is one mechanism that functions to maintain smoking in nicotine-dependent individuals. However, determining whether smoking or nicotine can truly enhance cognition, rather than simply provide withdrawal relief, can be difficult in smokers. Thus, we conducted two studies with nonsmokers. In the first study, we administered nicotine gum (0, 2, 4 mg) to nonsmokers during a single session. In the second study, we administered nicotine gum (0, 2, 4, 8 mg) to nonsmokers for 8 consecutive days. The data from both studies were consistent in finding no cognitive enhancing effects of nicotine. The data do not support the hypothesis that nicotine-induced cognitive enhancement contributes to the reinforcing effects of tobacco use during the early stages of nicotine dependence. We have also begun to explore the brain regions activated during performance of cognitive tests and the effect of nicotine on brain activation. The brain's response to a drug or cognitive test can be obtained from mapping studies in which measurement of regional cerebral blood flow (rCBF) via PET is used to infer function. In our first study, we measured cognitive activation during a working memory test in smokers, who abstained from smoking for 12 hours, and ex-smokers in two sessions, separated by one week. At one session, subjects received placebo gum, and at the other session, they received 4 mg nicotine gum before performing the memory test and the brain scan. The two-back test involved a series of letters presented individually, and target letters were those that matched a letter two back in the series. Compared to placebo, nicotine reduced errors on the two-back test in smokers, but had no effect on test performance in ex-smokers. The brain regions activated by the two-back test were consistent with those reported in the literature: dorsolateral prefrontal cortex, anterior cingulate gyrus, and inferior parietal cortex. However, in the placebo condition, rCBF activation in the ex-smokers predominated in the left hemisphere, and in smokers in the right hemisphere, suggesting differing cognitive strategies. When nicotine was administered, rCBF activation was enhanced in ex-smokers, but reduced in smokers, perhaps reflecting chronic tolerance.